Discovery & Approval
DRUG
Clinical trials divided into 3 phases: (require 6-9 years)
Phase 1
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Drug molecules drop to 5 compounds
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Apprx cost: 710 millions
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25% chance success
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Involving 20-100 healthy voluneteers
Phase II
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Drug molecules drop to 5 compounds
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Approx cost: 916 millions
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45% chance success
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Involving 100-300 disease patients
After IND application submission, FDA completes the review and if the application is aprroved, the next step is clinical trials studies.
Reference
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Ng, R. (2003) Clinical Trials, in Drugs: From Discovery to Approval, John Wiley & Sons, Inc., Hoboken, NJ, USA. doi: 10.1002/0471722804.ch6
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Health Canada, 2014, ‘About Health Canada’ modified at 27/2/2014, available from http://www.hc-sc.gc.ca/ahc-asc/index-eng.php
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Health Canada, 2013, ‘Clinical Trials and Drug Safety’ May 2013, available from http://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/clinical_trials-essais_cliniques-eng.php
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ADMINISTRATION, U. S. F. A. D. 2014. Conducting Clinical Trials [Online]. Available: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ConductingClinicalTrials/default.htm.
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Orlando.L (2014), '2014-Clinical Trilas-LO-140819', retireved from http://moodle.vle.monash.edu/pluginfile.php/3147562/mod_resource/content/0/2014-%20Clinical%20trials-LO-140819.pdf
Clinical Trials
Before clinical trials beign....
Before the trial is constructed, it is essential to have a proper consideration of ethical issues and protect all the trial subjects. The risk of human subjects should minimized and their benefit should be maximized. (Ng.R, 2003)
Therefore,
Independent review board(IRB) / lndependent ethics committee (IEC)
The IRB/IEC acts as a third party to oversee the welfare of the trial subjects and ensure that the trial is conducted in accordance to the study being put forward (Ng.R, 2003)
Members of IRB/IEC:
clinicians, scientists, lawyers, religious leaders and laypeople
represent different viewpoints and protect the rights of the subjects
formalised
Declaration of Helsinki
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Ethical Principles for Medical Research lnvolving Human Subjects
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describe the constraints on research involving human beings.
World Medical Association (WMA)
Clinical trials now shall begin...
Clinical trials consist of 3 stages:
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Phase I
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Phase II
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Phase III
Three Phases of Clinical Trials: (Ng.R, 2003)
Phase I
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The first experiment in which a drug is tested on the human body. (Ng.R, 2003)
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Conduct in healthy volunteers. (about 10 and 100 people)
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Aim: (i) Investigate the safety of the new drugs
(ii) Study pharmacokinetic (in particular ADME) & pharmacodynamic of the new drugs
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Using single or and multiple ascending dose study (SAD or MAD) (Orlando, L, 2014)
SAD : A small group of subjects are given a single dose of drug. The dose will increase time by time until subjects show intolerance side effect.
MAD: A small group of subjects are given low doses of the drugs, samples of blood, urine or stool and other physiological information are collected to analyze absorption, distribution, metabolism and elimination (ADME) of the drug in the body.
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Time : 6-12 months
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Cost: US$10 million
Phase II
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Target on disease patients. (about 50-500 patients)
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Aim: To examine the safety and effectiveness of the drug in patients.
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How:
(i) Patients are randomly assigned either the current standard treatment or placebo (an inert non-drug substance) without bias. The result collected can provide comparative data about the safety and
effectiveness of the drug versus placebo or standard treatment. (Ng.R, 2003)
(ii) Use a double-blind trial - patients are allocated to either recieve treatment of placebo by computer. This would further eliminating bias, making trial result more reliable. For double-blind trial, neither the
investigator nor the patient know the treatment received.
(iii) Another approach is to blind the product. The color, shape, size, weight, smell, taste, sound, touch should be no difference from one medicine to others. This blinding can be done in 2 ways either placebo matching and overcapsulation technique. This allows removing bias, making result more comparable.
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Time: 1-2 years
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Cost: more than US20 million.
Phase III
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Extension of Phase II
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Conducted in larger population of patients who have infectious diseases such as influenza or vaccines. (about 1000+ patients)
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Aim : To confirm drug effectiveness
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How:
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To establish statistical in order to analzye the data.
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Understanding safety and drug effectiveness.
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Provide information of dosage, treatment frequency, duration and target patient groups for the drug in order to to support marketing approval.
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Time: 3-5 years
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Cost: US$50-100 million.
Story hasn't ended....
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Phase III
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Drug molecules drop to 5 compounds
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Approx cost: 1.1 billions
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65% chance success
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Involving 1000-3000 disease patients
The United States National Institutes of Health
generates 7 ethical requirements:
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Social value
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Scientific validity
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Fair subject selection
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Informed consent
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Favorable risk-benefit ratio
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Independent review
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Respect for human subjects.
Always safeguard the rights, safety and well-being of all trial subjects
What if ethical consideration disappear ??
What will happen?
Real Story
In 2006, a drug, CD28 superagonist antibody TGN1412 confirmed as safe and efficacious in preclinical studies. It then conducted phase I clinical study in six human volunteers. Despite administered of a dose 500 times smaller than that found safe in animal studies, all six human volunteers faced life-threatening conditions involving multiorgan failure for which they were moved to intensive care unit.
Hence, this particular incident draw a conclusion on ethic and regulation are required to design a preclinical stidues that can better predict the risk in human.
Making all drugs look no difference.
Placing all the products such as tablet, capsules, caplets into an opaque capsule to prevent both investigators and human trials to distinguish between placebo or treatment.
Placebo Matching
Overcapsulation
The pharmacokinetics in humans show that this product may be effective when administered once daily.
Pharmacokinetics is defined as “the study of the kinetics of absorption, distribution, metabolism and excretion (ADME) of drugs. It analyses the way the human body deals with a drug after it has been administered, and the transportation of the drug to the specific site for drug-receptor interaction. (Ng.R, 2005) The pharmacokinetics in humans is carried out in clinical phase I to guide the safety, effectivity, and the dosing of the drug. In this question, it tells us that the information gathered from pharmacokinetics studies in human enable to estimate the duration of action of drug that is in its therapeutics window. In this case, the duration of action for this particular product is one day.
Q & A
Meet with Health Canada to explain your Phase III development program and obtain valuable suggestion for improvement.
Health Canada is “the Federal department responsible for helping Canadians maintain and improve their health, while respecting individual choices and circumstances”. (Health Canada, 2014). Phase III is extension of phase II in the clinical trials, aim for confirming the efficacy of the drug in 1000 and more larger patient population. (Ng.R 2003) In this case, the sponsor meets with Health Canada with their current clinical data to gain feedbacks and advice, in particular valuable suggestion for improvement phase III studies and the suitability of its Phase 3 development program to support a New Drug Submission ("NDS") in Canada.